(1) Field of the Invention
The present invention generally relates to live bacterial vaccines. More specifically, the invention is related to novel Mycobacterium sp. compositions, and the use of those compositions to protect mammals against disease caused by virulent Mycobacterium sp.
(2) Description of the Related Art
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U.S. Pat. No. 5,504,005.
There exists an urgent need for a novel tuberculosis (TB) vaccine as there are more than 8 million new cases of tuberculosis and more than 2 million deaths reported each year by the WHO (Dye et al., 1999). The discovery of the causative agent of TB, Mycobacterium tuberculosis, by Robert Koch in 1882 opened up the possibility for a novel vaccine (Koch, 1882). Since then, numerous attempts to develop attenuated vaccines against tuberculosis have failed, including tuberculin (a protein extract of killed tubercle bacilli) developed by Dr. Koch himself. This failure of tuberculin to protect led to a firm conviction that immunity could only be established by inducing a definite, albeit limited, tuberculosis process” Grange et al., 1983). Thus, numerous labs set out to follow the example of Dr. Louis Pasteur for viruses and enrich attenuated mutants of the tubercle bacillus following repeated passaging.
In order to test the hypothesis that a tubercle bacillus isolated from cattle (now known as M. bovis) could transmit pulmonary tuberculosis following oral administration, Drs. Calmette and Guerin developed a medium containing beef bile that enabled the preparation of fine homogenous bacillary suspensions (Calmette and Guerin, 1905). An M. bovis strain obtained from Dr. Norcard, was passaged every 21 days in this medium and after the 39th passage, the strain was found to be unable to kill experimental animal (Gheorghiu, 1996). “Between 1908 and 1921, the strain showed no reversion to virulence after 230 passages on bile potato medium” (Id.), which is consistent with the attenuating mutation being a deletion mutation. In the animal studies that followed, the strain (‘BCG’) was found to be attenuated but it also protected animals receiving a lethal challenge of virulent tubercle bacilli (Calmette and Guerin, 1920). BCG was first used as a vaccine against tuberculosis in 1921. From 1921 to 1927, BCG was shown to have protective efficacy against TB in a study on children (Weill-Halle and Turpin, 1925; Calmette and Plotz, 1929) and adopted by the League of Nations in 1928 for widespread use in the prevention of tuberculosis. By the 1950s after a series of clinical trials, the WHO was encouraging widespread use of BCG vaccine throughout the world (Fine and Rodrigues, 1990). Although an estimated 3 billion doses have been used to vaccinate the human population against tuberculosis, the mechanism that causes BCG s attenuation remains unknown.
Mahairas et al. (1996) first compared the genomic sequences of BCG and M bovis using subtractive hybridization and found that there were three major deletions (named RD1, RD2, and RD3) present in the genome of M. bovis, but missing in BCG. Behr et al. (1999) and others (Gordon et al., 2001) later identified 16 large deletions, including RD1 to RD3, present in the BCG genome but absent in M. tuberculosis. These authors concluded that 111 of these 16 deletions were unique to M. bovis, while the remaining 5 deletions were unique to BCG. They also found that one of these 5 deletions, designated RD1 (9454 bp), is present in all of the BCG substrains currently used as TB vaccines worldwide and concluded that the deletion of RD1 appeared to have occurred very early during the development of BCG, probably prior to 1921 (Behr et al., 1999).
The development of insertional mutagenesis systems for BCG and M. tuberculosis (Kalpana et al., 1991), transposon mutagenesis systems (Cirillo et al., 1991; McAdam et al., 1995; Bardarov et al., 1997) and allelic exchange systems (Balasubramanian et al., 1996; Pelicic et al., 1997) led to the isolation of the first auxotrophic (nutrient-requiring) mutants of these slow-growing mycobacteria. Auxotrophic mutants of BCG and M. tuberculosis have been shown to confer protection to M. tuberculosis challenges with variable efficacies (Guleria et al., 1996; Smith et al., 2001). However, a head-to-head comparison of BCG to a leucine auxotroph of BCG showed that a single immunization elicited no positive skin-test and imparted little immunity to challenges with M. tuberculosis or M. bovis (Chambers et al., 2000). In contrast, a methionine auxotroph of BCG that grows in vivo did confer significant protection to challenge to both M. tuberculosis and M. bovis (Id.). A single dose of a leucine auxotroph of M tuberculosis protected BALB/c mice as well as BCG in terms of survival post M. tuberculosis challenge yet was not as efficient as BCG at restricting the in vivo growth of the virulent bacilli (Hondalus et al., 2000). These results suggest that optimal immunity against M. tuberculosis requires some growth of the immunizing strain. Double mutants of M. tuberculosis have also been created (Parish and Stoker, 2000), but whether such mutants are improved over single attenuating mutants in protecting mammals against challenge with a virulent mycobacterium, particularly when the host is immunocompromised, has not been established.
It is also worth noting that in the study of Chambers et al. (2000), both BCG and the BCG mutants seemed to protect better against M. bovis challenge than M. tuberculosis. If we assume the reverse correlate is true, we could hypothesize that optimal immunity against M tuberculosis could be achieved with M. tuberculosis-derived mutant that grew in the mammalian host.
Based on the above, there remains a need for improved live mycobacterial vaccines having attenuated virulence, that confer protection from virulent mycobacteria, particularly M. tuberculosis. The instant invention satisfies that need.